Rate-Dependent Class III Antiarrhythmic Action, Negative Chronotropy, and Positive Inotropy of a Novel Ik Blocking Drug, UK-68,798

Tande, Pål M.; Bjørnstad, Hanne; Yang, Tao; Refsum, Helge

doi:10.1097/00005344-199009000-00008

Cited by 179 publications

(94 citation statements)

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“…First, in the rat, the repolarizing currents are dominated by I to with only a small contribution of I Kr . It is noteworthy that Tande et al did not observe a positive inotropic effect in rat papillary muscle with I Kr block [11]. Second, the inotropic effect of dofetilide is still observed under voltage clamp conditions that exclude indirect effects via changes in action potential duration.…”

Section: Does An Increase In Ncx Activity Have a Positive Inotropic Amentioning

confidence: 93%

“…The positive effects of I Kr block on contractility have been noted before [11,12] and ascribed to the well-known interaction between Ca handling and action potential duration. In cardiac cells, changes in amplitude and time course of the Ca transient will affect the action potential time course, and vice versa.…”

Section: Does An Increase In Ncx Activity Have a Positive Inotropic Amentioning

confidence: 94%

See 1 more Smart Citation

Dofetilide as Activator of Na/Ca Exchange: New Perspectives on an ‘Old’ Drug

Antoons

Sipido

2009

Cardiovasc Drugs Ther

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Section: Does An Increase In Ncx Activity Have a Positive Inotropic Amentioning

confidence: 93%

Section: Does An Increase In Ncx Activity Have a Positive Inotropic Amentioning

confidence: 94%

Dofetilide as Activator of Na/Ca Exchange: New Perspectives on an ‘Old’ Drug

Antoons

Sipido

2009

Cardiovasc Drugs Ther

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“…For this reason we have presented QT in three ways: uncorrected (QT), corrected according to Bazett's formula (QTc) and corrected according to Zbinden et al (1980) (Curtis & Hearse, 1989a). Binomially distributed variables were compared by the Chi2 test with Yates' correction where appropriate (Gad & Weil, 1989 (Gwilt et al, 1986;Tande et al, 1990).…”

Section: Arrhythmia Diagnosis and Ecg Analysismentioning

confidence: 99%

“…We have tested the hypothesis using a novel approach. We used a highly selective IK blocker (UK66,914) and compared its actions in rat and rabbit, making use of the fact that the rat ventricle is devoid of functional cardiac IK (Tande et al, 1990) whereas the rabbit possesses this current (Carmeliet, 1991).…”

Section: Control Uk66914mentioning

confidence: 99%

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Selective I_K blockade as an antiarrhythmic mechanism: effects of UK66,914 on ischaemia and reperfusion arrhythmias in rat and rabbit hearts

Rees

Curtis

1993

British J Pharmacology

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1 UK66,914 is a specific and selective blocker of the delayed rectifying potassium current (IK). The effectiveness of IK block as a mechanism for prevention of ischaemia-and reperfusion-induced arrhythmias was tested by use of UK66,914: its actions in rat, a species deficient in cardiac IK were compared with its actions in rabbit, a species possessing functional cardiac IK-Antiarrhythmic actions in rabbit but none in rat is the only outcome possible if selective IK blockade is responsible for the antiarrhythmic actions of the drug during ischaemia and/or reperfusion. 2 During 30 min regional ischaemia, 0.3 and 1 gM UK66,914 had no influence on the incidence of ventricular fibrillation (VF) in rat (n = 9/group), values being 78% in controls, 100% in 0.3 jM-treated hearts and 78% in 1.0 gM-treated hearts (NS). UK66,914 also had no effect on reperfusion-induced VF incidence (100% in each group), nor on the latency to onset of ischaemia-or reperfusion-induced arrhythmias. In contrast, in rabbit (n = 13/group), similar concentrations of drug reduced the incidence of reperfusion-induced VF from 77% in controls, to 38% and 31% (P <0.05) respectively. The incidence of ischaemia-induced arrhythmias was too low in controls to permit detection of an antiarrhythmic effect in rabbit; however no drug-induced proarrhythmia was seen. 3 QT interval was not affected by UK66,914 in rat (NS), values (mean ± s.e.mean) being 114 ± 8, 121 ± 8, and 113 ± 6 ms in control, 0.3 and 1 gM groups respectively, 10 min after the onset of ischaemia. However, in the rabbit the same concentrations of UK66,914 produced concentrationdependent widening of QT interval, values being 172 ± 14, 194 ± 9 (NS) and 233 ± 18 ms (P <0.05), with increasing concentrations of drug, 10 min after the onset of ischaemia. 4 UK66,914 had no substantial effects on haemodynamics (heart rate, coronary flow or recovery of flow during reperfusion), at either concentration, in either species. Occluded zones sizes were similar with increasing concentrations of drug in rat (42 ± 4, 40 ± 2 and 40 ± 2% of total ventricular weight) and rabbit (46 ± 2, 43 ± 2 and 46 ± 3%). Thus, the species-dependent antiarrhythmic effects of UK66,914 were not attributable to differences in these variables. 5 In conclusion, the rat versus rabbit data indicate that for UK66,914 to inhibit ventricular arrhythmias associated with reperfusion, IK blockade is sufficient and necessary. The rat data indicate that no antiarrhythmic effects occur with the drug during ischaemia when there is no scope for IK blockade. Whilst other mechanisms may be unlikely to be involved, they cannot be excluded completely. Together the rat and rabbit studies indicate that the antiarrhythmic effects of UK66,914 during ischaemia and reperfusion are adequately explained by IK blockade.

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Dai

Feng

et al. 1996

Drug Dev. Res.

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Rate-Dependent Class III Antiarrhythmic Action, Negative Chronotropy, and Positive Inotropy of a Novel Ik Blocking Drug, UK-68,798

Cited by 179 publications

References 0 publications

Dofetilide as Activator of Na/Ca Exchange: New Perspectives on an ‘Old’ Drug

Dofetilide as Activator of Na/Ca Exchange: New Perspectives on an ‘Old’ Drug

Selective I_K blockade as an antiarrhythmic mechanism: effects of UK66,914 on ischaemia and reperfusion arrhythmias in rat and rabbit hearts

Blockade on sodium, potassium, and calcium channels by a new antiarrhythmic agent CPU 86017

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Rate-Dependent Class III Antiarrhythmic Action, Negative Chronotropy, and Positive Inotropy of a Novel Ik Blocking Drug, UK-68,798

Cited by 179 publications

References 0 publications

Dofetilide as Activator of Na/Ca Exchange: New Perspectives on an ‘Old’ Drug

Dofetilide as Activator of Na/Ca Exchange: New Perspectives on an ‘Old’ Drug

Selective IK blockade as an antiarrhythmic mechanism: effects of UK66,914 on ischaemia and reperfusion arrhythmias in rat and rabbit hearts

Blockade on sodium, potassium, and calcium channels by a new antiarrhythmic agent CPU 86017

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Selective I_K blockade as an antiarrhythmic mechanism: effects of UK66,914 on ischaemia and reperfusion arrhythmias in rat and rabbit hearts